Abstract
Age-related hearing impairment (ARHI), one of the most common sensory disorders, can be mitigated, but not cured or eliminated. To identify genetic influences underlying ARHI, we conducted a genome-wide association study of ARHI in 6,527 cases and 45,882 controls among the non-Hispanic whites from the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort. We identified two novel genome-wide significant SNPs: rs4932196 (odds ratio = 1.185, p = 4.0x10-11), 52Kb 3’ of ISG20, which replicated in a meta-analysis of the other GERA race/ethnicity groups (1,025 cases, 12,388 controls, p = 0.00094) and in a UK Biobank case-control analysis (30,802 self-reported cases, 78,586 controls, p = 0.015); and rs58389158 (odds ratio = 1.132, p = 1.8x10-9), which replicated in the UK Biobank (p = 0.00021). The latter SNP lies just outside exon 8 and is highly correlated (r2 = 0.96) with the missense SNP rs5756795 in exon 7 of TRIOBP, a gene previously associated with prelingual nonsyndromic hearing loss. We further tested these SNPs in phenotypes from audiologist notes available on a subset of GERA (4,903 individuals), stratified by case/control status, to construct an independent replication test, and found a significant effect of rs58389158 on speech reception threshold (SRT; overall GERA meta-analysis p = 1.9x10-6). We also tested variants within exons of 132 other previously-identified hearing loss genes, and identified two common additional significant SNPs: rs2877561 (synonymous change in ILDR1, p = 6.2x10-5), which replicated in the UK Biobank (p = 0.00057), and had a significant GERA SRT (p = 0.00019) and speech discrimination score (SDS; p = 0.0019); and rs9493627 (missense change in EYA4, p = 0.00011) which replicated in the UK Biobank (p = 0.0095), other GERA groups (p = 0.0080), and had a consistent significant result for SRT (p = 0.041) and suggestive result for SDS (p = 0.081). Large cohorts with GWAS data and electronic health records may be a useful method to characterize the genetic architecture of ARHI.
Highlights
Age-related hearing impairment (ARHI), or presbycusis, is one of the most common sensory impairments [1,2], affecting 25% of individuals over age 65 and 50% of individuals over age 80 [3]
It is hoped that identification of genetic influences on ARHI may one day lead to curative therapies
The second was in TRIOBP, a gene previously associated with prelingual nonsyndromic hearing loss
Summary
Age-related hearing impairment (ARHI), or presbycusis, is one of the most common sensory impairments [1,2], affecting 25% of individuals over age 65 and 50% of individuals over age 80 [3]. The effects of ARHI can be mitigated by amplification devices and assistive listening devices, but it is not curable and the effects cannot be completely eliminated. The best hope for cure lies in identifying all the physiologic and environmental factors contributing to ARHI and developing interventions that address these risks. There are a number of contributing factors to ARHI, including early noise exposure, medication history, and genetics [1,5,6,7,8,9,10,11]. It is hoped that by identifying the genetic basis of ARHI, targeted therapies can be developed to mitigate this risk
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